Prolonged activity of the transposase helper may raise safety concerns during DNA transposon-based gene therapy

Imre, Gergely; Takács, Bertalan; Czipa, Erik; Drubi, Andrea Bakné; Jaksa, Gábor; Latinovics, Dóra; Nagy, Andrea; Karkas, Réka; Hudoba, Liza; Vásárhelyi, Bálint Márk; Pankotai-Bodó, Gabriella; Blastyák, András; Hegedűs, Zoltán; Germán, Péter; Bálint, Balázs; Abdullah, Khaldoon Sadiq Ahmed; Kopasz, Anna Georgina; Kovács, Anita; Nagy, László G.; Sükösd, Farkas; Pinter, L.; Rülicke, Thomas; Barta, Endre; Nagy, István; Haracska, Lajos; Mátés, Lajos

doi:10.1016/j.omtm.2023.03.003

Cited by 4 publications

(12 citation statements)

References 68 publications

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“…Furthermore, Similarities have been observed in some of the electronic properties of CNT (7,6) when DNA nucleobases were applied around its external environment and encapsulated cases. Such that the band gap energy differences (ΔE gap ) for both cases (encapsulated and outer side environment) follows the pattern: CNT (7, 6) + G > CNT (7, 6) + C > CNT (7, 6) + A > CNT (7, 6) + T. The results revealed that in the encapsulated cases the ΔE gap decreased from 0.48 to 0.21 eV for G nucleobase and from 0.384 to 0.18 eV for C nucleobase.…”

Section: Calculation Methodssupporting

confidence: 54%

“…Calculations of electronic properties were performed at room temperature (300 K). Optimized structures of DNA nucleobases, chiral CNTs (CNT (7,6), CNT (8,6), and CNT (10, 8)), and encapsulated CNTs with DNA nucleobases are shown in Figs. 1 and 2.…”

Section: Calculation Methodsmentioning

confidence: 99%

“…The use of DFTB method is very convenient for systems containing the high number of atoms and the possibility of using DFT is associated with heavy computational costs. First, we designed the DNA nucleobases and pristine chiral CNT (7,6), CNT (8,6), and CNT (10,8) individually in the simulation unit cell. Then we started energies and forces convergence for structural optimization steps.…”

Section: Calculation Methodsmentioning

confidence: 99%

“…CNTs based on their chiral indices can be divided into three electronic categories (metals, insulators, and semiconductors) [44][45][46] . Due to band gap energy values for chiral CNT (7,6), CNT (8,6), and CNT (10,8), they are classified as semiconductors. In addition, by increasing the diameter of the CNTs from 8.84 to 12.28 Å, the band gap energy has decreased due to the quantum confinement effect 47,48 .…”

Section: Calculation Methodsmentioning

confidence: 99%

“…We also considered DNA nucleobases encapsulation effects inside the selected chiral CNTs. Three chiral CNT (7,6), CNT (8,6), and CNT (10,8), which can be synthesized experimentally, were selected. For sequencing, we examined some of the most important electronic parameters such as band structure, band gap, electron density of states (DOS), and absorption energy.…”

mentioning

confidence: 99%

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A DFTB study on the electronic response of encapsulated DNA nucleobases onto chiral CNTs as a sequencer

Monavari,

Memarian

2024

Sci Rep

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Sequencing the DNA nucleobases is essential in the diagnosis and treatment of many diseases related to human genes. In this article, the encapsulation of DNA nucleobases with some of the important synthesized chiral (7, 6), (8, 6), and (10, 8) carbon nanotubes were investigated. The structures were modeled by applying density functional theory based on tight binding method (DFTB) by considering semi-empirical basis sets. Encapsulating DNA nucleobases on the inside of CNTs caused changes in the electronic properties of the selected chiral CNTs. The results confirmed that van der Waals (vdW) interactions, π-orbitals interactions, non-bonded electron pairs, and the presence of high electronegative atoms are the key factors for these changes. The result of electronic parameters showed that among the CNTs, CNT (8, 6) is a suitable choice in sequencing guanine (G) and cytosine (C) DNA nucleobases. However, they are not able to sequence adenine (A) and thymine (T). According to the band gap energy engineering approach and absorption energy, the presence of G and C DNA nucleobases decreased the band gap energy of CNTs. Hence selected CNTs suggested as biosensor substrates for sequencing G and C DNA nucleobases.

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Section: Calculation Methodssupporting

confidence: 54%

Section: Calculation Methodsmentioning

confidence: 99%

Section: Calculation Methodsmentioning

confidence: 99%

Section: Calculation Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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A DFTB study on the electronic response of encapsulated DNA nucleobases onto chiral CNTs as a sequencer

Monavari,

Memarian

2024

Sci Rep

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Stable transduction of the neonatal mouse liver using a hybrid rAAV/sleeping beauty transposon gene delivery system

Cunningham,

Zakas,

Sasaki

et al. 2024

The Journal of Gene Medicine

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BackgroundConventional adeno‐associated viral (AAV) vectors, while highly effective in quiescent cells such as hepatocytes in the adult liver, confer less durable transgene expression in proliferating cells owing to episome loss. Sustained therapeutic success is therefore less likely in liver disorders requiring early intervention. We have previously developed a hybrid, dual virion approach, recombinant AAV (rAAV)/piggyBac transposon system capable of achieving stable gene transfer in proliferating hepatocytes at levels many fold above conventional AAV vectors. An alternative transposon system, Sleeping Beauty, has been widely used for ex vivo gene delivery; however liver‐targeted delivery using a hybrid rAAV/Sleeping Beauty approach remains relatively unexplored.MethodsWe investigated the capacity of a Sleeping Beauty (SB)‐based dual rAAV virion approach to achieve stable and efficient gene transfer to the newborn murine liver using transposable therapeutic cassettes encoding coagulation factor IX or ornithine transcarbamylase (OTC).ResultsAt equivalent doses, rAAV/SB100X transduced hepatocytes with high efficiency, achieving stable expression into adulthood. Compared with conventional AAV, the proportion of hepatocytes transduced, and factor IX and OTC activity levels, were both markedly increased. The proportion of hepatocytes stably transduced increased 4‐ to 8‐fold from <5%, and activity levels increased correspondingly, with markedly increased survival and stable urinary orotate levels in the OTC‐deficient Spfash mouse following elimination of residual endogenous murine OTC.ConclusionsThe present study demonstrates the first in vivo utility of a hybrid rAAV/SB100X transposon system to achieve stable long‐term therapeutic gene expression following delivery to the highly proliferative newborn mouse liver. These results have relevance to the treatment of genetic metabolic liver diseases with neonatal onset.

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Sleeping Beauty mRNA-LNP enables stable rAAV transgene expression in mouse and NHP hepatocytes and improves vector potency

Zakas,

Cunningham,

Doherty

et al. 2024

Molecular Therapy

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Prolonged activity of the transposase helper may raise safety concerns during DNA transposon-based gene therapy

Cited by 4 publications

References 68 publications

A DFTB study on the electronic response of encapsulated DNA nucleobases onto chiral CNTs as a sequencer

A DFTB study on the electronic response of encapsulated DNA nucleobases onto chiral CNTs as a sequencer

Stable transduction of the neonatal mouse liver using a hybrid rAAV/sleeping beauty transposon gene delivery system

Sleeping Beauty mRNA-LNP enables stable rAAV transgene expression in mouse and NHP hepatocytes and improves vector potency

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